Association of colorectal cancer susceptibility variants with tumor subtypes in three large prospective cohorts.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 445-445 ◽  
Author(s):  
Xabier Garcia-Albeniz ◽  
Hongmei Nan ◽  
Charles S. Fuchs ◽  
Edward L. Giovannucci ◽  
Jing Ma ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lower Risk ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Tumor Stage ◽  
Health Study ◽  
Genome Wide Association Studies ◽  
Case Control Studies ◽  
Tumor Subtypes ◽  
T Stage

445 Background: Genome-wide association studies (GWAS) have identified 17 colorectal cancer (CRC) susceptibility variants. However, their association with specific tumor subtypes has not been fully defined. Methods: We genotyped (TaqMan OpenArray) 17 variants (rs6691170, rs6687758, rs10936599, rs11169552, rs7136702, rs6983267, rs16892766, rs10795668, rs3802842, rs4444235, rs4779584, rs9929218, rs4939827, rs10411210, rs961253 , rs7014346 and rs2151512 as proxy of rs4925386) in three independent prospective, CRC case-control studies nested within the Nurses’ Health Study, Health Professionals Follow-up Study, and Physicians Health Study cohorts (1227 cases, 2201 age- and race-matched controls). Genotyping success: 98.1%. All variants fitted HWE (P>0.05). We assessed the association of these variants with risk of CRC using logistic regression (LR) adjusted for age, race and study under an additive model. We used multinomial LR models to examine the association of variants to CRC according to T, N and M-stage, grade of differentiation, tumor site, and age at diagnosis. Heterogeneity in the associations were evaluated by a case-case only LR model. Results: We observed associations with CRC for rs6983267 (OR 0.86, 95% CI, 0.77-0.95; p=0.0028 -T allele-), rs3802842 (OR 1.18; 95% CI, 1.05-1.31; p=0.0036 -C allele-), rs7014346 (OR 1.15, 95% CI, 1.04-1.28, p=0.0082 -A allele-), rs11169552 (OR 0.88, 95% CI 0.78-0.99 -T allele-) and rs4939827 (OR 0.90, 95%CI 0.82-1.00, p=0.0508 – C allele-). The association between rs4939827 (MAF 48.34%) and risk of CRC was significantly different according to T stage (p for heterogeneity < 0.0001). rs4939827 was associated with a lower risk of CRC with tumor stage T1 or T2 (OR, 0.72; 95% CI, 0.63-0.84, p<.0001) but not of cancers with tumor stage T3 or T4 (OR, 1.04; 95% CI, 0.92-1.19). This result is consistent within each cohort. Conclusions: Among 17 CRC susceptibility variants, we observed that the minor allele of rs4939827 was associated with a lower risk of colorectal cancers with lower T stage but not higher T stage. These results suggest that rs4939827, which codes for an intronic region of SMAD7, may be mechanistically related to tumor invasiveness.

Known colorectal cancer susceptibility loci and survival after colorectal cancer diagnosis.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 394-394 ◽  
Author(s):  
Amanda Phipps ◽  
Xabier Garcia-Albeniz ◽  
Carolyn Hutter ◽  
Emily White ◽  
Charles S. Fuchs ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Fixed Effects ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Cox Proportional Hazards ◽  
Health Study ◽  
Genome Wide Association Studies ◽  
Increased Risk

394 Background: Beyond clinicopathologic stage, there are few established markers of prognosis in colorectal cancer (CRC). Recent genome-wide association studies have identified 17 germline single nucleotide polymorphisms (SNPs) significantly associated with incident CRC. However, it is unclear if these CRC susceptibility SNPs influence survival after CRC diagnosis. Although the functionality of many of these SNPs remains unknown, a few, including rs4939827 in SMAD7, map to genes with plausible biological mechanisms associated with both cancer risk and prognosis. We examined 17 CRC susceptibility SNPs in relation to survival after CRC diagnosis. Methods: We genotyped 2,611 men and women enrolled in five prospective cohort studies who were diagnosed with invasive CRC during study follow-up: the Physicians’ Health Study (N=281), Health Professionals Follow-up Study (N=268), Nurses’ Health Study (N=367), Vitamins and Lifestyle Study (N=281), and the Women’s Health Initiative (N=1414). Analyses were limited to Caucasians with known vital status, cause of death, and survival time. We used Cox proportional hazards regression to assess associations between each SNP and CRC-specific and overall survival in study-specific models adjusted for age, sex, and stage; SNPs were modeled additively to reflect associations per copy of the minor allele. Study-specific results were combined via fixed-effects meta-analysis. Results: The G allele in rs4939827 was associated with poorer CRC-specific survival [hazard ratio (HR)=1.16, p=0.02] and overall survival (HR=1.13, p=0.03) in CRC patients. The A alleles in rs10795668 and in rs4925386 were associated with a 1.14-fold increased risk of overall mortality (both p-values=0.03) but not CRC-specific mortality. Other evaluated SNPs were not associated with survival. Conclusions: Genetic variation in rs4939827 (SMAD7) is associated with CRC-specific and overall survival. These results suggest that SMAD7 may have a role in CRC progression, and provide proof-of-principle that common germline variation may provide prognostic information beyond traditional considerations such as stage.

scholarly journals Common variants in breast cancer risk loci predispose to distinct tumor subtypes

2019 ◽  
Author(s):  
Thomas U. Ahearn ◽  
Haoyu Zhang ◽  
Kyriaki Michailidou ◽  
Roger L. Milne ◽  
Manjeet K. Bolla ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Growth Factor Receptor ◽  
Breast Cancer Susceptibility ◽  
Genome Wide Association Studies ◽  
Luminal A ◽  
Logistic Regression Models ◽  
Multiple Tumor ◽  
Tumor Subtypes

AbstractGenome-wide association studies (GWAS) have identified over 170 common breast cancer susceptibility variants using standard GWAS methods. Many of these variants have differential associations by estrogen receptor (ER), but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. We used two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Eighty-five of 178 variants were associated with at least one tumor feature (false discovery rate <5%), most commonly ER and grade followed by PR and HER2. Case-control comparisons among these 85 variants identified 65 variants strongly or exclusively associated (P<0.05) with luminal-like subtypes, 5 variants associated with all subtypes at differing strengths and 15 variants primarily associated with non-luminal subtypes, especially triple-negative (TN) disease. Five variants were associated with risk of Luminal A-like and TN subtypes in opposite directions. This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility loci and can inform investigations of subtype-specific risk prediction.

scholarly journals The Role of Colorectal Cancer Risk Chromosomal Regions in Colombian Admixed Populations

2018 ◽  
Vol 4 (Supplement 2) ◽  
pp. 207s-207s
Author(s):  
A. Criollo-Rayo ◽  
M. Bohórquez ◽  
P. Lott ◽  
A. Carracedo ◽  
I. Tomlinson ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Demographic History ◽  
Recessive Model ◽  
Genome Wide Association Studies ◽  
Increased Risk ◽  
Risk Snps ◽  
Population Demographic

Background: Several colorectal cancer susceptibility disease loci have been discovered through genome-wide association studies. However most of the variants were originally identified in Caucasian populations. Aim: To analyze the role of 20 known risk SNPs for colorectal cancer. Methods: Given that linkage disequilibrium is highly dependent on population demographic history and admixture background, we studied 20 risk SNPs in a pooled sample of 955 cases and 968 controls from admixed populations in Colombia. Results: The replication was reached for 11 out of 20 nominally associated SNPs; with allelic odds ratios (OR) ranging from 1.14 to 1.41, indicating a minimal increase in risk individually, however coinheritance of those SNPs resulted in an overall OR = 5.4 (95% CI: 3.052-9.731, P = 1.16E−08). Most of the variants followed a recessive model consistent with significant homozygous ORs distributed between 1.3 and 1.65. Among the most associated markers we found: rs4939827 (18q21.1, P = 7.35E−6), rs10411210 (19q13.11, P = 0.001), rs10795668 (10p14, P = 0.0024), rs4444235 (14q.2.2, P = 0.005), rs961253 (20p12.3, P = 0.006), rs16892766 (8q23.3, P = 0.011) and rs1050547 (8q24.21, P = 0.017). Conclusion: Our findings in Colombia have addressed the admixture and how this has influenced the risk associated with the known/unknown colorectal cancer regions, providing a comprehensive vision about several CRC-susceptibility SNPs identified in European populations, which also resulted, associated with an increased risk to CRC in the Colombian population, even though frequency and genetic structure differences accounted for those nonreplicated SNPs.

scholarly journals GWAS Links New Variant in Long Non-Coding RNA LINC02006 with Colorectal Cancer Susceptibility

Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 465
Author(s):  
Ewa E. Hennig ◽  
Anna Kluska ◽  
Magdalena Piątkowska ◽  
Maria Kulecka ◽  
Aneta Bałabas ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Bioinformatic Analysis ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Tumor Invasiveness ◽  
Non Coding Rna ◽  
New Variant ◽  
Long Non Coding Rna

Despite great efforts, most of the genetic factors contributing to the risk of colorectal cancer (CRC) remain undetermined. Including small but homogenous populations in genome-wide association studies (GWAS) can help us discover new common risk variants specific to the studied population. In this study, including 465 CRC patients and 1548 controls, a pooled DNA samples-based GWAS was conducted in search of genetic variants associated with CRC in a Polish population. Combined with a new method of selecting single-nucleotide polymorphisms (SNPs) for verification in individual DNA samples, this approach allowed the detection of five new susceptibility loci not previously reported for CRC. The discovered loci were found to explain 10% of the overall risk of developing CRC. The strongest association was observed for rs10935945 in long non-coding RNA LINC02006 (3q25.2). Three other SNPs were also located within genes (rs17575184 in NEGR1, rs11060839 in PIWIL1, rs12935896 in BCAS3), while one was intergenic (rs9927668 at 16p13.2). An expression quantitative trait locus (eQTL) bioinformatic analysis suggested that these polymorphisms may affect transcription factor binding sites. In conclusion, four of the identified variants were located within genes likely involved in tumor invasiveness and metastasis. Therefore, they could possibly be markers of poor prognosis in CRC patients.

scholarly journals Relevance of hMLH1 -93G>A, 655A>G and 1151T>A polymorphisms with colorectal cancer susceptibility: a meta-analysis based on 38 case-control studies

2018 ◽  
Vol 64 (10) ◽  
pp. 942-951 ◽  
Author(s):  
Mohammad Zare ◽  
Jamal Jafari-Nedooshan ◽  
Mohammadali Jafari ◽  
Hossein Neamatzadeh ◽  
Seyed Mojtaba Abolbaghaei ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Susceptibility ◽  
Meta Analysis ◽  
Asian Population ◽  
Case Control ◽  
Biomedical Literature ◽  
Case Control Studies ◽  
Increased Risk ◽  
Comprehensive Search ◽  
Meta Analyses

SUMMARY OBJECTIVE: There has been increasing interest in the study of the association between human mutL homolog 1 (hMLH1) gene polymorphisms and risk of colorectal cancer (CRC). However, results from previous studies are inconclusive. Thus, a meta-analysis was conducted to derive a more precise estimation of the effects of this gene. METHODS: A comprehensive search was conducted in the PubMed, EMBASE, Chinese Biomedical Literature databases until January 1, 2018. Odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of the association. RESULTS: Finally, 38 case-control studies in 32 publications were identified met our inclusion criteria. There were 14 studies with 20668 cases and 19533 controls on hMLH1 −93G>A, 11 studies with 5,786 cases and 8,867 controls on 655A>G and 5 studies with 1409 cases and 1637 controls on 1151T>A polymorphism. The combined results showed that 655A>G and 1151T>A polymorphisms were significantly associated with CRC risk, whereas −93G>A polymorphism was not significantly associated with CRC risk. As for ethnicity, −93G>A and 655A>G polymorphisms were associated with increased risk of CRC among Asians, but not among Caucasians. More interestingly, subgroup analysis indicated that 655A>G might raise CRC risk in PCR-RFLP and HB subgroups. CONCLUSION: Inconsistent with previous meta-analyses, this meta-analysis shows that the hMLH1 655A>G and 1151T>A polymorphisms might be risk factors for CRC. Moreover, the −93G>A polymorphism is associated with the susceptibility of CRC in Asian population.

Principles of endocrinology

2018 ◽  
pp. 1-24
Author(s):  
Helen E. Turner ◽  
Richard Eastell ◽  
Ashley Grossman
Keyword(s):  
Multiple Endocrine Neoplasia ◽  
Hormone Receptors ◽  
Association Studies ◽  
Endocrine System ◽  
Endocrine Disorders ◽  
Genome Wide Association Studies ◽  
Linkage Studies ◽  
Case Control Studies ◽  
Related Case ◽  
Genome Wide

This chapter discusses the principles of endocrinology, starting with a description of the anatomy of endocrine glands, hormone structures, and hormone receptors. It similarly provides information on hormone measurements, such as immunoassays, mass spectrometry, hormonal-binding proteins, and biological matrices from serum, urine, and saliva. It relates autoimmunity to the endocrine system, and provides examples of studies of genetic endocrine disorders, such as linkage studies, complex endocrine disease-related case control studies, and genome-wide association studies. Providing information on the endocrine epidemiology, this chapter describes ethnic and geographic variation in disorders such as iodine deficiency, thyroid cancer, vitamin D deficiency, pituitary disease, diabetes, and multiple endocrine neoplasia.

scholarly journals Critical Analysis of Genome-Wide Association Studies: Triple Negative Breast Cancer Quae Exempli Causa

2020 ◽  
Vol 21 (16) ◽  
pp. 5835
Author(s):  
Maria-Ancuta Jurj ◽  
Mihail Buse ◽  
Alina-Andreea Zimta ◽  
Angelo Paradiso ◽  
Schuyler S. Korban ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Risk Factors ◽  
Genetic Risk ◽  
Triple Negative ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Breast Cancer Susceptibility ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Genome Wide

Genome-wide association studies (GWAS) are useful in assessing and analyzing either differences or variations in DNA sequences across the human genome to detect genetic risk factors of diseases prevalent within a target population under study. The ultimate goal of GWAS is to predict either disease risk or disease progression by identifying genetic risk factors. These risk factors will define the biological basis of disease susceptibility for the purposes of developing innovative, preventative, and therapeutic strategies. As single nucleotide polymorphisms (SNPs) are often used in GWAS, their relevance for triple negative breast cancer (TNBC) will be assessed in this review. Furthermore, as there are different levels and patterns of linkage disequilibrium (LD) present within different human subpopulations, a plausible strategy to evaluate known SNPs associated with incidence of breast cancer in ethnically different patient cohorts will be presented and discussed. Additionally, a description of GWAS for TNBC will be presented, involving various identified SNPs correlated with miRNA sites to determine their efficacies on either prognosis or progression of TNBC in patients. Although GWAS have identified multiple common breast cancer susceptibility variants that individually would result in minor risks, it is their combined effects that would likely result in major risks. Thus, one approach to quantify synergistic effects of such common variants is to utilize polygenic risk scores. Therefore, studies utilizing predictive risk scores (PRSs) based on known breast cancer susceptibility SNPs will be evaluated. Such PRSs are potentially useful in improving stratification for screening, particularly when combining family history, other risk factors, and risk prediction models. In conclusion, although interpretation of the results from GWAS remains a challenge, the use of SNPs associated with TNBC may elucidate and better contextualize these studies.

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